The present invention relates generally to novel purine and pyrimidine compounds which have antiviral activity and methods of making and using same.
Viruses are the etiologic cause of many life-threatening human diseases. Of special importance are herpes viruses such as herpes simplex 1 (HSV-1), herpes simplex 2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and human herpes virus 6 (HHV 6) which are associated with many common viral illnesses. The HSV-1 and HSV-2 infections are characterized by cold sores of skin, mouth or genital region. After primary infection the virus is harbored in neural cells and can reappear later in the life of a patient. Human CMV (HCMV) infection is a life-long affliction which can result in morbidity and mortality. These pathologies include microcephaly, hepatosplenomegaly, jaundice, encephalitis, infections of the newborn infants or fetuses in utero, and infections of immunocompromised hosts. The HCMV infection is responsible for retinitis, gastritis and pneumonitis in AIDS patients and HCMV-induced pneumonias or hepatitis are frequent and serious complications of bone marrow transplants. EBV causes infectious mononucleosis and it is considered as the etiologic agent of nasopharyngeal cancer, immunoblastic lymphoma, Burkitt""s lymphoma and hairy leukoplakia. VZV causes chicken pox and shingles. Although in children the chicken pox is usually a non-fatal disease, the recurrent form of this infection, shingles, may in advanced stage lead to paralysis, convulsions and ultimately death. Again, in immunocompromised patients the infection with VZV is a serious complication. Human herpes virus 6 (HHV-6) which is commonly associated with children""s rash was also identified in acquired immunodeficiency syndrome (AIDS) patients and it may be a cofactor in the pathogenesis of AIDS in hosts infected with human immunodeficiency virus (HIV). Levine, A. J., Viruses, Ch. 4, W. H. Freeman and Co., New York, pp. 67-85 (1992); Human Herpesvirus Infections, Raven Press, New York (1986).
HIV is the underlying cause of AIDS, a world-wide epidemic with fatal consequences. According to the World Health Organization, over 4.5 million AIDS cases were recorded by late 1994 and 19.5 million people had been infected with HIV. It is estimated that by the year 2000, 30 to 40 million will have been infected with HIV with 10 million cases of full-blown AIDS. Estimates of Global AIDS Policy Coalition are considerably higherxe2x80x94up to 110 million HIV infections and 25 million AIDS cases. The Relationship between the Human Immunodeficiency Virus and the Acquired Immunodeficiency Syndrome, The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., pp. 1-3 (1995).
Various alkyl derivatives of purines and pyrimidines and analogues thereof have been found to exhibit antiviral activity. Notably, acyclovir (Zovirax) and ganciclovir (Cytovene) belonging to this group of compounds are approved drugs for infections caused by HSV-1, HSV-2, VZV and HCMV. Acyclovir Therapy for Herpesvirus Infections (Baker, Ed.), M. Dekker, New York, (1990); Ganciclovir Therapy for Cytomegalovirus Infection (Spector, S. S., Ed.), M. Dekker, New York (1991). A considerable effort went into design, synthesis and biological investigation of analogues of these drugs as well as in development of new antiviral agents. Larsson, A., et al., Antimicrob. Agents and Chemother. 30:598-605 (1986); Ashton, W. T., et al., J. Med. Chem. 31:2304-2315 (1988).
Current drugs for AIDS include AZT (zidovudine, Retrovir), ddl (didanosine, Videx), ddC (zalcitabine, Hivid) and d4T (stavudine, Zerit). De Clercq, E., J. Med. Chem. 38:2491-2517 (1995). Allenic nucleoside analogues such as adenallene and cytallene are examples of anti-HIV agents containing an unsaturated alkyl group. U.S. Pat. No. 4,935,427; Zemlicka, J., Allenols Derived from Nucleic Acid Basesxe2x80x94a New Class of Anti-HIV Agents:Chemistry and Biological Activity in Nucleosides and Nucleotides as Antitumor and Antiviral Agents (Chu, C. K.; Baker, D. C., Eds.), Plenum Press, New York, pp. 73-100 (1993).
It would thus be desirable to provide novel compounds which are active against viruses, including HCMV, HSV-1, HSV-2, HHV-6, HIV, hepatitis B virus (HBV), and other mammalian viruses.
The present invention provides novel 2-hydroxymethylcyclopropylidenemethyl-derivatives of heterocyclic compounds, prodrugs and pharmacologically acceptable acid salts thereof. These compounds have been found to be useful antiviral agents and are effective against HCMV, HSV-1, HSV-2, HHV-6, HIV, EBV and HBV, as well as against other mammalian viruses.
The compounds of the present invention have the following Formulas: 
wherein
B is a heterocyclic ring derived from a purine or pyrimidine moiety. In a preferred embodiment, the purine moieties include 6-aminopurine (adenine), 2,6-diaminopurine, 2-amino-6-azidopurine, 2-amino-6-thiopurine, 2-amino-6-alkylaminopurines such as 2-amino-6-cyclopropylaminopurine, 6-hydroxypurine (hypoxanthine), 2-amino-6-halo substituted purines, such as 2-amino-6-chloropurine, 2-amino-6-alkoxy substituted purines, such as 2-amino-6-methoxypurine, 2-amino-6-hydroxypudne (guanine), 3-deazapurines, 7-deazapurines, 8-azapurines, cytosine, 5-halo substituted cytosines, 5-alkyl substituted cytosines, thymine, uracil and 6-azapyrimidines.
Prodrugs of the antiviral nucleoside analogues of the present invention include lipophilic phosphate esters or amidates capable of penetrating the cell membrane. Those skilled in the art will appreciate that the aim of prodrugs is to provide effective therapeutic agents for resistant strains of viruses (McGuigan, C., et al., J. Med. Chem. 36:1048-1052 (1993)) or activate inactive analogues. Franchetti, P., et al., J. Med. Chem. 37:3534-3541 (1994).
The compounds of the present invention therefore also include prodrugs of the novel compounds, wherein the prodrugs have the following Formulas: 
wherein
B is a heterocyclic ring as defined above for Formulas 1 and 2;
X is O; and
R1 and R2 are alkyl or aryl. The R1X or R2X may also be amino acid residues with X as NH.
Compositions useful for treating viral infections, such as HCMV, HSV-1, HSV-2, HHV-6, HIV, EBV and HBV contain an effective amount of at least one compound of Formulas 1 to 4 or a pharmaceutically acceptable salt thereof.
The present invention also includes methods for synthesizing compounds of Formulas 1 and 2 wherein B is a heterocyclic ring derived from purine or pyrimidine moiety such as 6-aminopurine (adenine), 2,6-diaminopurine, 2-amino-6-azidopurine, 2-amino-6-thiopurine, 2-amino-6-alkylaminopurines such as 2-amino-6-cyclopropylaminopurine, 6-hydroxypurine (hypoxanthine), 2-amino-6-halo substituted purines, such as 2-amino-6-chloropurine, 2-amino-6-alkoxy substituted purines, such as 2-amino-6-methoxypurine, 2-amino-6-hydroxypurine (guanine), 3- and 7-deazapurines, such as 3- and 7-deazaadenine, 8-azapurines such as 8-azaadenine, cytosine, 5-halocytosine (wherein halo is bromo, chloro, iodo or fluoro) and related alkyl derivatives containing a saturated or unsaturated alkyl group at the 5-position, thymine, uracil, 6-azapyrimidines such as 6-azacytosine, wherein the alkyl side-chain attached to the heterocyclic ring is a 2-hydroxymethylcyclopropyiidenemethane moiety.
The present invention also provides methods for synthesizing prodrugs of the compounds as set forth in Formulas 3 and 4.
The present invention also provides methods for synthesizing essentially enantiomerically pure R- and S-enantiomers of the compounds of the present invention.
Additional objects, advantages, and features of the present invention will become apparent from the following description, taken in conjunction with the accompanying drawings.